文献：cRGD target liposome delivery system promoted immunogenic cell death through enhanced anticancer potency of a thymidine conjugate under UVA activation as a cancer vaccine

文献链接：https://www.sciencedirect.com/science/article/pii/S022352341930145X

作者：

Rong Yang 1, Zhiwei Wang 1, Ying Yuan, Ting Qian, Qibing Zhou

摘要：

Conventional chemotherapeutic and photodynamic therapy have recently been shown to also elicit immune response against cancer through the immunogenic cell death mechanism, which can be potentially translated into effective cancer vaccines. However, there are few studies on the potential of nanodelivery system to promote the immunogenic cell death as a cancer vaccine. We reported here that cRGD target liposome delivery system was capable to promote the immunogenic cell death through enhanced potency of a thymidine conjugate post UVA activation as a cancer vaccine. Liposomes and cRGD target liposomes were found to significantly increase the cellular accumulation of the thymidine conjugate and subsequently translated into enhanced cytotoxic potency after UVA activation. More importantly, cRGD target liposomes of the thymidine conjugate markedly promoted the early detection of immunogenic cell death markers including ATP, HMGB1 and calreticulin. Subsequent in vivo vaccination−challenge study confirmed effective tumor growth inhibition by the cRGD liposomal thymidine conjugate and UVA treated cancer cells as the cancer vaccine. In addition, liposomes and cRGD target liposomes alone did not shown any induction of the immunogenic cell death markers, revealing the adjuvant nature of the nanodelivery system.

DSPE-PEG-cRGD的合成

向溶于2:3甲醇和水（500μL）的DSPE-PEG马来酰亚胺（3.64mg）中加入磷酸缓冲盐水（PBS，200 μL).所得混合物在室温下反应过夜，然后用10 mL甲醇。用制备型HPLC C18柱（内径20mm）分离所需产物 × 150 mm，GS-120-10-C18-AP，和0.1%三氟乙酸在MeOH中的洗脱液（3μL/min）。收集的DSPE-PEG-cRGD为脱色油状物（1.96mg，44%收率），并通过1H NMR和质谱分析进行确认。

对于cRGD靶脂质体，通过硬脂酰马来酰亚胺的共轭硫醇加成合成了硬脂酰-PEG-cRGD共轭物（DSPE-PEG-cRGD），该共轭物易于通过HPLC分离分离，并通过1H NMR和MS分析得到证实）。cRGD脂质体的制备方法与DSPC脂质体相似。为了优化cRGD靶向的有效性，在两种具有代表性的癌症细胞系MCF-7和Bel-7402上研究了DSPE-PEG-cRGD比DSPE-PEG比例增加的脂质体 细胞。

MCF-7 免疫荧光研究首次证实，细胞表面cRGD靶αv和β3整合素水平高于Bel-7402 细胞。然后基于2Cl化合物的荧光特性，通过荧光显微镜分析评估2Cl化合物在这两个细胞系中的积累。显然，在MCF-7中发现了最高的荧光 与具有较低量的非靶向脂质体和2Cl对照的细胞相比，具有高量cRGD脂质的细胞。

在贝尔-7402 高比率cRGD脂质体似乎比其他脂质体产生更高的荧光强度。DSPC脂质体系统中DSPE-PEG-cRGD量的进一步增加导致纳米颗粒尺寸增加超过100 nm和2Cl化合物负载量差。因此，cRGD脂质体被优化为含0.15 μmol/mL DSPE-PEG-cRGD用于以下表征和生物学研究。空和2Cl负载的cRGD脂质体的平均粒径为90 nm，ζ电位分别显著增加至+14.3和+15.9 mV。

所得带正电的cRGD脂质体与非靶向脂质体和其他报道的通常带负电的脂质体形成对比，这可能是由于与PEG部分连接的长疏水烷基硫醇链的存在。2Cl的装载效率为8.3 nmol/mL为81.2%。此外，空的和负载的cRGD靶脂质体在超过72小时的血清存在下是稳定的 h。最后，TEM分析证实了2Cl纳米颗粒、DSPC脂质体和cRGD-DSPC脂质体在没有和有2Cl负载的情况下的生产，其流体动力学尺寸是一致的。

相关推荐产品：

DSPE-PEG-Glucose

DSPE-PEG-Glutamic acid

DSPE-PEG-Glycine triarginine

DSPE-PEG-His

DSPE-PEG-Mannose,DSPE-PEG-Man

DSPE-PEG-Methyltetrazine

DSPE-PEG-MTX

DSPE-PEG-nano gold

DSPE-PEG-NB

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